Genetic control of astrocyte function in neural circuits

Abstract

During the last two decades numerous genetic approaches affecting cell function in vivo have been developed. Current state-of-the-art technology permits the selective switching of gene function in distinct cell populations within the complex organization of a given tissue parenchyma. The tamoxifen-inducible Cre/loxP gene recombination and the doxycycline-dependent modulation of gene expression are probably the most popular genetic paradigms. Here, we will review applications of these two strategies while focusing on the interactions of astrocytes and neurons in the central nervous system (CNS) and their impact for the whole organism. Abolishing glial sensing of neuronal activity by selective deletion of glial transmitter receptors demonstrated the impact of astrocytes for higher cognitive functions such as learning and memory, or the more basic body control of muscle coordination. Interestingly, also interfering with glial output, i.e., the release of gliotransmitters can drastically change animal’s physiology like sleeping behavior. Furthermore, such genetic approaches have also been used to restore astrocyte function. In these studies two alternatives were employed to achieve proper genetic targeting of astrocytes: transgenes using the promoter of the human glial fibrillary acidic protein (GFAP) or homologous recombination into the glutamate-aspartate transporter (GLAST) locus. We will highlight their specific properties that could be relevant for their use.

Astrocyte function from information processing to cognition and cognitive impairment

“…A number of promoters such as hGFAP, GLAST, GLT1, CX43 and FGF3, are considered selectively active in astrocytes 142 . However, their efficiency can vary greatly between astrocytes and between brain regions 143 and it can be useful to verify their expression for the defined CNS area (for example using reporters such as GFP) and animal age of interest.…”

GLAST‐CreERT2mediated deletion ofGDNFincreases brain damage and exacerbates long‐term stroke outcomes after focal ischemic stroke in mouse model

“…Mouse numbers were indicated in the figures. *p < .05, **p < .005, ***p < .0005, ANOVA test [Color figure can be viewed at wileyonlinelibrary.com] mouse lines and astrocyte-specific adeno-associate virus (AAV) for gene deletion and overexpression (Jahn, Scheller, & Kirchhoff, 2015;Xie et al, 2010), dissection of exclusive roles of astrocytes in neuronal circuit and neuronal degeneration/death becomes feasible. GLAST-CreER T2 mediated recombination has been used to express florescent reporters to study the morphology of astrocytes and Ca 2+ signaling in astrocytes, and label adult-born granule cell lineage (Bardehle et al, 2013;DeCarolis et al, 2013;Paukert et al, 2014).…”

Phloretin‐induced cytoprotective effects on mammalian cells: A mechanistic view and future directions

“…BDNF is an important neurotrophin involved in various events related to neuronal plasticity necessary to maintain memory function and dynamics [68,69]. Therefore, by exhibiting an antioxidant effect, by decreasing the levels of GFAP (a neuroinflammatory marker [70,71]), and by augmenting the contents of a neurotrophin possessing crucial neuromodulatory roles, phloretin caused neuroprotection in an amnesia experimental model. The complete mechanism was not showed by the authors, but possibly includes modulation of cell signaling de Oliveira pathways and transcription factors that upregulate BDNF and downregulate GFAP expressions, as previously reported [72,73].…”